title: A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease.
abstract: Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γc(null) mice under the influence of activated CLL-derived T lymphocytes. By co-transferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4(+) T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity.
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Bagnara
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Kaufman
authors.forename: Carlo
authors.initials: C
authors.lastname: Calissano
authors.forename: Sonia
authors.initials: S
authors.lastname: Marsilio
authors.forename: Piers E M
authors.initials: PE
authors.lastname: Patten
authors.forename: Rita
authors.initials: R
authors.lastname: Simone
authors.forename: Philip
authors.initials: P
authors.lastname: Chum
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Sivasubramanian
authors.initials: S
authors.lastname: Baskar
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.forename: Hakan
authors.initials: H
authors.lastname: Mellstedt
authors.forename: Hodjattallah
authors.initials: H
authors.lastname: Rabbani
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000097:blood; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018448:Models, Immunological; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014182:Transplantation, Autologous; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D008562:Membrane Glycoproteins; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1